Obstructive sleep apnea (OSA), a disorder causing intermittent nocturnal hypoxia and sleep fragmentation, and associated with metabolic disorders, affects 3-5% of adults. OSA episodes are particularly severe during REM sleep, when postural atonia occurs and the level of activity in upper airway dilator muscles reaches a nadir. The goal of this project is to understand the neural mechanisms of upper airway hypotonia during REM sleep. Using a pharmacological (carbachol) model of REM sleep, we determined that the atonia of hypoglossal (XlI) motoneurons that innervate an important upper airway dilator is caused by the loss of serotonergic and noradrenergic excitation, whereas antagonism of inhibitory amino acid receptors unveils an excitatory effect of REM sleep on Xll motoneurons. The role of serotonin is well established. In contrast, the source of the noradrenergic drive and the mechanisms of REM sleep-related excitation are unknown. Our studies of projections to the Xll nucleus lead us to hypothesize that: (1) REM sleep-related loss of noradrenergic activation originates in pontine A7 neurons; (2) neurons of the ventromedial medullary reticular formation (v-mMRF), a major target of axonal projections from the pontine REM sleep-triggering region, mediate inhibitory effects; and (3) REM sleep-related excitatory input originates in inspiratory Xll premotor neurons located in the intermediate medullary reticular region (IRt). To test our hypothesis, we propose four Specific Aims (SA). SA1: Determine whether noradrenergic A7 neurons are silenced during the atonia of REM sleep and have axonal ramifications in the Xll nucleus. In anesthetized rats, we will record from A7 neurons during carbachol-induced REM sleep-like atonia and conduct antidromic mapping of their projections. SA2: Determine whether Xll premotor neurons located in the v-mMRF are activated during carbachol-induced atonia and are inhibitory to Xll motoneurons. SA3: Characterize serotonergic, noradrenergic, and cholinergic receptor mRNA and protein expression in Xll premotor neurons of the IRt. SA4: Functionally assess responses of inspiratory Xll premotor neurons of the IRt to iontophoretic application of selective serotonergic, noradrenergic and cholinergic receptor agonists and antagonists. The proposed studies will define the role of three important brainstem sources of REM sleep-related inputs to Xll motoneurons. This should help design new pharmacologic treatments for OSA. [unreadable] [unreadable]